Newborn and juvenile eyes have an emmetropization mechanism that uses visual signals to precisely adjust the axial length of the eyes to the optical power, so that images are in sharp focus. However, nearly 30% of the U.S. population develops axial myopia, in which the eyes are elongated relative to the focal plane. Although glasses, contact lenses and refractive surgery can provide an optical correction, the increased axial length of the eye significantly raises the risk of retinal detachment, choroidal neovascularization and glaucoma, making myopia the 7th leading cause of blindness in the U.S. The emmetropization mechanism has at least three main components: 1) the retina, which responds to the sign and amount of defocus (or other visual cues);2) a signaling cascade that originates in the retina, travels through the retinal pigment epithelium (RPE) and choroid, and reaches the sclera (the fibrous outer coat of the eye);and 3) fibroblasts in the sclera which respond to the signaling cascade by regulating the axial length. Our working hypothesis is that retinal responses to visual stimuli control the remodeling of the scleral extracellular matrix and, in particular, the slippage of the layers (lamellae) of the sclera across each other. This, in turn, controls scleral extensibility, axial elongation, and refractive state. The proposed studies will examine the retinal responses to visual stimuli and the scleral responses to the signaling cascade. In the previous project period, we identified two novel "dissociation" paradigms in which similar visual stimuli produce different scleral responses due to the prior history of the eye (somewhat longer or shorter than normal, an "eye-size" factor). Specific Aims 1 and 2 will use these dissociative paradigms to test our hypothesis that the source of this variability is localized in the patterns of gene expression in the sclera, rather than in the retina, and to identify the specific scleral signaling pathways that are involved. Specific Aim 3 will use an "association" paradigm in which three different methods (darkness, form deprivation, and minus-lens wear) will be used to induce myopia to identify the pattern of retinal gene expression that is common to all three and contributes to the "retina go" response. The proposed studies will apply proteomic tools and our "Pathway-focused PCR Assay" that have been developed in this laboratory to assess retinal mRNA and protein-expression patterns that characterize retinal go and retina stop responses, and scleral mRNA and protein-expression patterns that characterize the sclera go, sclera stop and sclera ignores responses in our well-characterized animal model, tree shrew. These animals are closely related to primates and, like humans, have an all-fibrous sclera. These studies will enhance our understanding the emmetropization mechanism at the level of gene expression and may lead to successful optical or pharmacological interventions to slow or prevent myopia. PUBLIC HEALTH RELEVANCE Myopia (nearsightedness) affects over 25% of the U.S. population and perhaps one billion people worldwide. In addition to the cost (over $14 billion annually) of eye exams, glasses, contact lenses, and refractive surgery, even low amounts of myopia raise the risk of developing blinding conditions. This application will identify genes and gene products that control the axial length of the eye as a step toward finding ways to prevent or minimize myopia in children.